TY - JOUR

T1 - Knock-out of the critical nitric oxide synthase regulator DDAH1 in mice impacts amphetamine sensitivity and dopamine metabolism

AU - Козлова, Алёна Алексеевна

AU - Рубец, Елена

AU - Vareltzoglou, Magdalini R

AU - Jarzebska, Natalia

AU - Ragavan, Vinitha N.

AU - Chen, Yingjie

AU - Martens-Lobenhoffer, Jens

AU - Bode-Böger, Stefanie M

AU - Гайнетдинов, Рауль Радикович

AU - Rodionov, Roman N

AU - Bernhardt, Nadine

PY - 2023/9

Y1 - 2023/9

N2 - The enzyme dimethylarginine dimethylaminohydrolase 1 (DDAH1) plays a pivotal role in the regulation of nitric oxide levels by degrading the main endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). Growing evidence highlight the potential implication of DDAH/ADMA axis in the etiopathogenesis of several neuropsychiatric and neurological disorders, yet the underlying molecular mechanisms remain elusive. In this study, we sought to investigate the role of DDAH1 in behavioral endophenotypes with neuropsychiatric relevance. To achieve this, a global DDAH1 knock-out (DDAH1-ko) mouse strain was employed. Behavioral testing and brain region-specific neurotransmitter profiling have been conducted to assess the effect of both genotype and sex. DDAH1-ko mice exhibited increased exploratory behavior toward novel objects, altered amphetamine response kinetics and decreased dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) level in the piriform cortex and striatum. Females of both genotypes showed the most robust amphetamine response. These results support the potential implication of the DDAH/ADMA pathway in central nervous system processes shaping the behavioral outcome. Yet, further experiments are required to complement the picture and define the specific brain-regions and mechanisms involved.

AB - The enzyme dimethylarginine dimethylaminohydrolase 1 (DDAH1) plays a pivotal role in the regulation of nitric oxide levels by degrading the main endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). Growing evidence highlight the potential implication of DDAH/ADMA axis in the etiopathogenesis of several neuropsychiatric and neurological disorders, yet the underlying molecular mechanisms remain elusive. In this study, we sought to investigate the role of DDAH1 in behavioral endophenotypes with neuropsychiatric relevance. To achieve this, a global DDAH1 knock-out (DDAH1-ko) mouse strain was employed. Behavioral testing and brain region-specific neurotransmitter profiling have been conducted to assess the effect of both genotype and sex. DDAH1-ko mice exhibited increased exploratory behavior toward novel objects, altered amphetamine response kinetics and decreased dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) level in the piriform cortex and striatum. Females of both genotypes showed the most robust amphetamine response. These results support the potential implication of the DDAH/ADMA pathway in central nervous system processes shaping the behavioral outcome. Yet, further experiments are required to complement the picture and define the specific brain-regions and mechanisms involved.

KW - Amphetamine

KW - Behaviour

KW - DDAH1

KW - Dopamine

KW - Knock-out mice

KW - Nitric oxide

KW - Nitric Oxide Synthase/genetics

KW - Amphetamine/pharmacology

KW - Genotype

KW - Nitric Oxide/metabolism

KW - Enzyme Inhibitors/pharmacology

KW - Mice, Knockout

KW - Animals

KW - Female

KW - Amidohydrolases/genetics

KW - Mice

UR - https://www.mendeley.com/catalogue/985377d4-cc96-34ec-b2ba-ef0d569b5835/

U2 - 10.1007/s00702-023-02597-7

DO - 10.1007/s00702-023-02597-7

M3 - Article

C2 - 36792833

VL - 130

SP - 1097

EP - 1112

JO - Journal of Neural Transmission - Parkinson's Disease and Dementia Section

JF - Journal of Neural Transmission - Parkinson's Disease and Dementia Section

SN - 0936-3076

IS - 9

ER -